Though novel therapeutic interventions and passive immunization will have vital, roles to play in biodefense, there is no substitute for pre-existing immunity to the major threats. Unfortunately, for most infectious agents it is not currently feasible to provide rapid administration of vaccines that elicit adequate protection. Moreover, any immunization program should have both a high level of safety and public acceptance. We envision a response strategy that includes live attenuated enteric bacterial vaccines. These vaccines would be very safe, and would elicit both mucosal and systemic responses. Alone, they would protect many exposed to bioattack, perhaps within one week of immunization. Those adequately protected would likely be those experiencing small, natural levels of exposure, such as postal workers handling contaminated mail. However, it is anticipated that some victims would be exposed to a supra-normal inoculum, presumably by the aerosol or gastrointestinal route. For these individuals, a protective vaccination regimen could include priming with the mucosal agent, followed by on-demand boosting with a parenterally administered subunit vaccine. After boosting, the recipients would be expected to generate fast, vigorous, balanced immune responses, which would protect them at the level of the mucosa and via both Th1 and Th2 systemic components. This application requests support for final pre-clinical development of a Salmonella-based platform technology, the ultimate intent of which is to provide protection against anthrax and plague in a single vaccine, combined with protection against typhoid fever provided by the vector itself. This portion of the anthrax/plague product development plan focuses on development of the plague component. By the conclusion of this award, we will be ready for clinical trials which are expected to result in clinically and economically effective vaccine candidates. This work will be pursued in four phases: Phase 1. Final construction of a human-ready vaccine. This will include stabilization of the heterologous antigen expression plasmid in the absence of antibiotic selection (currently forbidden by the FDA). Phase 2. Demonstration of immunogenicity of the vaccine candidates constructed under Phase 1. Constructs will be tested in our standardized mouse model for induction of serum IgG. Phase 3. Demonstration of efficacy of the final human-ready vaccine candidate in aerosol challenge models of plague. These studies will be performed by subcontract at Battelle. Phase 4. Perform preclinical studies and develop a clinical plan. This will include preparation of the pre-IND packet, the pre-IND meeting, formalizing support from the clinical sponsor, and performance of all studies mandated by the FDA in the pre-IND meeting. By the conclusion of this award, we will be prepared to initiate clinical trials of one or more vaccine candidates.